To simplify the analysis of asthma susceptibility genes located at human chromosome 5q23-35, we examined congenic mice that differed at the homologous chromosomal segment. We identified a Mendelian trait encoded by T cell and Airway Phenotype Regulator (Tapr). Tapr is genetically distinct from known cytokine genes and controls the development of airway hyperreactivity and T cell production of interleukin 4 (IL-4) and IL-13. Positional cloning identified a gene family that encodes T cell membrane proteins (TIMs); major sequence variants of this gene family (Tim) completely cosegregated with Tapr. The human homolog of TIM-1 is the hepatitis A virus (HAV) receptor, which may explain the inverse relationship between HAV infection and the development of atopy.

SMAD4 (MAD homologue 4 (Drosophila)), also known as DPC4 (deleted in pancreatic cancer), is a tumour suppressor gene that encodes a central mediator of transforming growth factor-beta signalling. Germline mutations in SMAD4 are found in over 50% of patients with familial juvenile polyposis, an autosomal dominant disorder characterized by predisposition to hamartomatous polyps and gastrointestinal cancer. Dense inflammatory cell infiltrates underlay grossly normal appearing, non-polypoid colonic and gastric mucosa of patients with familial juvenile polyposis. This prominent stromal component suggests that loss of SMAD4-dependent signalling in cells within the epithelial microenvironment has an important role in the evolution of intestinal tumorigenesis in this syndrome. Here we show that selective loss of Smad4-dependent signalling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumours arising within the colon, rectum, duodenum, stomach and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4(-/-) T cells produce abundant T(H)2-type cytokines including interleukin (IL)-5, IL-6 and IL-13, known mediators of plasma cell and stromal expansion. The results support the concept that cancer, as an outcome, reflects the loss of the normal communication between the cellular constituents of a given organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours.

The structure of the Fab of McPC 603, a mouse myeloma protein with phosphorylcholine binding activity has been determined to 3.1-A resolution. The four domains are found to be structurally similar with a well-defined double-layer structure. A large cavity exists at one end of the fragment, the walls of which are formed exclusively of hypervariable residues. Phosphorylcholine binds in this cavity and forms specific interactions with several well-defined amimo-acid side chains of the protein.The hapten is bound asymmetrically and interacts more with the heavy chain than with the light chain.We have been investigating the nature of antibody-antigen interactions by means of a crystallographic investigation of the Fab fragments of mouse myeloma proteins with known binding specificity (1, 2). The testing of myeloma proteins in mice for antigen-binding activity has revealed that many of them interact by precipitation, agglutination, or complementfixation with common natural antigens from the environment of the mouse (3, 4). Immunochemical analysis of myeloma protein-antigen interactions has in many cases led to the identification of the chemical group (hapten) on the antigen molecule.Antibodies, induced to dextran, levan, and phosphorylcholine in mice, share cross-specific antigenic (idiotypic) determinants with myeloma proteins of corresponding specificity (5, 6; M. Potter and R. Lieberman, unpublished observations). These findings strongly suggest the close relationship of antigen-binding myeloma proteins in mice to natural or induced antibodies. One of these myeloma proteins, from McPC 603, precipitates with antigens from several pathogenic organisms, and has been demonstrated to bind specifically to phosphorylcholine (3). We have previously reported crystallization of the Fab fragment of McPC 603 protein (1) and its structure at 4.5-A resolution together with the location of its phosphorylcholine-binding site (2). Here we present the results of a 3.1-structure determination and the molecular details of phosphorylcholine binding. We compare these results with the crystallographic results on a human Fab fragment with hydroxyvitamin K1 binding properties (7,8), and with two human Bence-Jones proteins (9, 10). MATERIALS AND METHODSThe preparation and crystallization of McPC 603 pepsin Fab has been described (1). The (pH 7.0). They belong to the space group P6N with a = b = 162.5, c = 60.8 A. Heavy atom derivatives were prepared by soaking the crystals in solutions containing TmCl,, K2Pt(CNS)6, iodine, and combinations of these

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Immunoglobulin (Ig) isotype switching is a recombination event that changes the constant domain of antibody genes and is catalyzed by activation-induced cytidine deaminase (AID). Upon recruitment to Ig genes, AID deaminates cytidines at switch (S) recombination sites, leading to the formation of DNA breaks. In addition to their role in isotype switching, AIDinduced lesions promote Igh-cMyc chromosomal translocations and tumor development. However, cMyc translocations are also present in lymphocytes from healthy humans and mice, and thus, it remains unclear whether AID directly contributes to the dynamics of B cell transformation. Using a plasmacytoma mouse model, we show that AID +/ ؊ mice have reduced AID expression levels and display haploinsuffi ciency both in the context of isotype switching and plasmacytomagenesis. At the Ig loci, AID +/ ؊ lymphocytes show impaired intra-and interswitch recombination, and a substantial decrease in the frequency of S mutations and chromosomal breaks. In AID +/ ؊ mice, these defects correlate with a marked decrease in the accumulation of B cell clones carrying Igh-cMyc translocations during tumor latency. These results thus provide a causality link between the extent of AID enzymatic activity, the number of emerging Igh-cMyc -translocated cells, and the incidence of B cell transformation.

Plasmacytoma (PCT) cell lines dependent for proliferation and survival on a factor elaborated by the murine macrophage cell line, P388D1, were established in vitro. Adherent peritoneal cells induced by pristane produced 50-fold greater amounts of this activity in vitro than did resident cells. The molecules responsible for plasmacytoma growth were distinct from a number of characterized factors including interleukin-1, -2, and -3, macrophage colony-stimulating factor, B-cell stimulatory factor-1, B-cell growth factor II, epidermal growth factor, transforming growth factor-beta, and gamma- and beta-interferon, none of which were able to support the growth of the factor-dependent PCT cell lines. These results suggest that PCT growth factor may be a novel factor that has not been previously characterized and, further, that its production is associated with the pristane-induced, chronic peritoneal inflammatory response that precedes plasmacytoma formation.

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